Introduction

In June 2011, Janssen Pharmaceuticals Inc notified healthcare providers of a pegylated liposomal doxorubicin (PLD) shortage. Shortcomings in quality assurance were identified during a good manufacturing practice (GMP) inspection at the manufacturing site—Ben Venue Laboratories in Ohio, USA. Ben Venue decided to cease all manufacture and distribution of medicines from its site, affecting the availability of several oncology medicines, notably PLD, for which Ben Venue was the only manufacturing source.

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended that PLD supplies should be available to patients already on treatment but no new patients start treatment with PLD until further notice. Unfortunately, this situation was maintained throughout the whole of last year.

The lack of PLD was of particular concern for the treatment of relapsed ovarian cancer (ROC), as PLD is indicated, in monotherapy, for the treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen [1] and, in combination with trabectedin, for the treatment of platinum-sensitive ROC [2].

All the oncologists who treat ROC were facing a very difficult situation, looking for alternative therapies in the treatment of a disease in which, even with PLD, there is a high medical need for new and effective agents.

After more than a year and a half, this difficult situation has come to an end. Janssen’s manufacturing solution involves a new collaboration between different suppliers to complete end-to-end production of PLD. Finally, relief greeted the news in October 2012 that PLD would become fully available in Europe and the US in 2013.

The full availability of PLD leads ovarian cancer patients to benefit again from this treatment, as monotherapy (widely used for the treatment of platinum-resistant disease) or in combination with trabectedin.

The return of trabectedin + PLD combination is particularly relevant for those patients for whom platinum is not the best treatment option. Although the standard treatment of platinum-sensitive recurrent ovarian cancer consists of platinum-based combination chemotherapy, for some patients retreatment with platinum is not the most convenient therapy:

• partially platinum-sensitive patients (platinum-free interval (PFI) between 6 and 12 months)
• patients having developed hypersensitivity to platinum
• patients suffering residual cumulative toxicities from previous platinum.

Partially platinum-sensitive disease

There is not a clear consensus in the treatment of partially platinum-sensitive relapsed ovarian cancer, where response rates to further platinum are in the 25‒30% range [3].

Trabectedin + PLD was the first non-platinum-based combination approved by the European Commission for the treatment of platinum-sensitive ROC. This combination has shown a 6-month improvement in median survival relative to singleagent PLD (22.4 months vs 16.4 months; HR = 0.64; p = 0.0027) in patients with partially platinum-sensitive disease [4].

Preclinical and clinical data indicate that, in relapsed ovarian cancer, the artificial expansion of PFI with an intervening nonplatinum therapy may be beneficial, possibly by reversing platinum resistance, which may be of particular interest to patients with partially platinum-sensitive disease [3].

The overall survival (OS) data of partially platinum-sensitive patients who received a platinum containing regimen directly after trabectedin + PLD treatment were analyzed, showing an extreme OS effect with 9 months difference compared to PLD and a 42% decrease in the risk of death (HR: 0.58; 27.7 vs 18.7 months; p = 0.0153), see Figure 1 [5].

*Figure 1 pending to upload.

These results strongly suggest the use of trabectedin + PLD as second-line treatment followed by a platinum regimen as third line for the treatment of partially platinum-sensitive relapsed ovarian cancer [5].

Hypersensitivity to platinum

Patients with recurrent epithelial ovarian cancer are frequently retreated with carboplatin for platinum-sensitive recurrent disease (PFI > 12 months). Repeated exposure to carboplatin can lead to hypersensitivity reactions (HSR) during retreatment with carboplatin, this may prevent its further use in platinum-sensitive ovarian cancer patients. Treatment of acute reactions with antihistamines and corticosteroids is often required. There is, however, the possibility of severe cardio pulmonary compromise, and even death, despite aggressive resuscitative efforts [6].

Desensitization protocols are often used to treat patients who have already developed HSR during retreatment. However, even with the utilization of such protocols, HSR patients may still be unable to receive further carboplatin or cisplatin [6].

For this reason, in recurrent epithelial ovarian cancer, where treatment is non-curative and several alternative non-platinumbased options exist, experts must weigh the risks and benefits of further carboplatin treatment [6].

In sensitive patients (PFI > 12 months) trabectedin + PLD has shown an OS of 36.5 months, in the range of that obtained with platinum combinations, which makes it a valuable option for patients with platinum-sensitive disease, who have developed hypersensitivity reactions to platinum [7-13].

Residual cumulative toxicities related to previous platinum treatments

Recognition of recurrent ovarian cancer as a disease with significant secondary responses and remissions has led to an increase in the need for oncologists to plan for the long-term therapy of patients. Carboplatin and cisplatin are the current standards of care of platinum-sensitive ovarian cancer, but their long-term toxicities present challenges in the retreatment of patients with relapsed ovarian cancer [14].

Cisplatin is associated with several cumulative toxicities, including dose-dependent renal tubule toxicity and neurotoxicity. Neurotoxicity, including paresthesias and permanent high-tone hearing loss, occurs in up to 23% and 45% of patients receiving cisplatin therapy, respectively. In addition, the risk of an allergic hypersensitivity response increases with continued use [14].

Carboplatin causes dose-limiting and cumulative myelosuppression, characterized by frequent and severe thrombocytopenia, granulocytopenia, and anaemia. Although cumulative myelosuppression is the main toxicity associated with carboplatin, there is also a significant risk of neurotoxicity and hypersensitivity reactions [14].

The irreversible effects associated with these therapies may render patients less tolerant to subsequent treatments and lead to a cycle of diminishing treatment options with each remission and disease relapse. Additionally, the potential for patients to experience cumulative toxicity must be carefully weighed against the goals of prolonging the disease-free interval and improving patient quality of life [14].

Unlike established platinum and taxane-based regimens, trabectedin + PLD has a predictable and manageable safety profile, associated with greatly diminished incidence of neuropathy and alopecia, as well as a lack of end organ, cumulative toxic effects [15, 16].

In the treatment of platinum-sensitive ovarian cancer, when platinum is not the best option, trabectedin + PLD is the alternative.

Author

Josep M del Campo, MD
Director of Gynecological, Head and Neck Cancer Division
Department of Medical Oncology
Vall d’Hebron University Hospital
119-129 Pg Vall d’Hebron
ES-08035 Barcelona, Spain

References

1. European Medicines Agency [homepage on the Internet]. Caelyx summary of product characteristics. 2012 [2013 Feb 21]. Available from: http://www.emea.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000089/WC500020180.pdf
2. European Medicines Agency [homepage on the Internet]. Yondelis summary of product characteristics. 2013 [2013 Feb 21]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_ Product_Information/human/000773/WC500045832.pdf
3. Poveda A, Vergote I, Tjulandin S, Kong B, Roy M, Chan S, et al. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol. 2011 Jan;22(1):39-48.
4. Monk B, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al. Trabectedin plus pegylated liposomal doxoru-bicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis. Eur J Cancer. 2012;48(15):2361-8.
5. Colombo A. Locally advanced cervical carcinoma-chemoradiation treatment. Int J Gynecol Cancer. 2011 Oct;21(suppl 3):1.
6. O’Cearbhaill R, Zhou Q, Iasonos A, Hensley ML, Tew WP, Aghajanian C, et al. The prophylactic conversion to an extended infusion schedule and use of premedication to prevent hypersensitivity reactions in ovarian cancer patients during carboplatin retreatment. Gynecol Oncol. 2011;116(3):326-31.
7. Monk BJ, et al. Activity of docetaxel plus trabectedin in recurrent or persistent ovarian and primary peritoneal cancer: a phase II study of the Gynecologic Oncology Group (GOG). J Clin Oncol. 2010;28(Suppl 15):abstract 5046.
8. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361(9375):2099-106.
9. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol. 2010;28(20):3323-9.
10. Gladieff L, Ferrero A, De Rauglaudre G, Brown C, Vasey P, Reinthaller A, et al. Carboplatin and pegylated liposomal doxoru-bicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial. Ann Oncol. 2012; 23(5):1185-9.
11. Wagner U, Marth C, Largillier R, Kaern J, Brown C, Heywood M, et al. Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Cancer. 2012;107(4):588-91.
12. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without beva-cizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-45.
13. Aghajanian C, et al. Updated overall survival analysis in oceans, a randomized phase 3 trial of gemcitabine (G) + car-boplatin (C) and bevacizumab (BV) or placebo (PL) followed by BV or PL in platinum-sensitive recurrent epithelial ovarian (ROC), primary peritoneal (PPC), or fallopian tube cancer (FTC). Ann Oncol. 2012;23(Suppl 9):ix319–ix33. Abstract 967O.
14. Dunton CJ. Management of treatment-related toxicity in advanced ovarian cancer. Oncologist. 2002;7(Suppl 5):11-9.
15. Sehouli J, Alfaro V, González-Martín A. Trabectedin plus pegylated liposomal doxorubicin in the treatment of patients with partially platinum-sensitive ovarian cancer: current evidence and future perspectives. Ann Oncol. 2012;23(3):556-62.
16. González Martín A. Safety profile of trabectedin in combination with liposomal pegylated doxorrubicin in relapsed ovarian carcinoma: considerations for optimal management. Int J Gynecol Cancer. 2011 May;21(Suppl 1):S6-8.